Induced phase transition method for the production of microparticles containing hydrophobic active agents

Abstract

Microparticles and a method for their production is described. The process of the present invention provides a simple, quick, and efficient one-pot process for the production of microparticles containing a non-water soluble active agent. The microparticles are preferably used for pharmaceutical applications and comprise at least 80 wt % microspheres.

Description

CROSS REFERENCES TO RELATED APPLICATION[0001]This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 60 / 257,527, filed Dec. 31, 2000, and U.S. Provisional Patent Application Ser. No. 60 / 300,021, filed Jun. 21, 2001, the disclosures of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention is directed to a process for the production of microparticles containing a non-water soluble biologically active, as well as the microparticles produced by this process. According to the invention, a simplified one-pot process for producing such microparticles is provided.BACKGROUND OF THE INVENTION[0003]Many biologically active drugs possess strong lipophilic properties, which result in negligible solubility in water. The development of an appropriate formulation of these active substances therefore is a challenging problem.[0004]One alternative to currently available formulations of these pharmacologically active substances is...

AI Technical Summary

Benefits of technology

[0046]The present invention provides a novel, simple and mild process for the encapsulation of non-water soluble active agents in biodegradable polymers which avoids or reduces the disadvantages seen in the prior art. The process produces non-agglomerating, microparticles in the size range from 20 nm to 1,000 μm at encapsulation efficiencies of greater than 85%, preferably greater than 90% using toxicologically acceptable solvents. The process of the present invention employs a minimal volume of surfactant solution resulting in a reduced production time compared with other prior art processes. Additionally, the process according to the invention may be readily scaled up to meet commercial-scale production needs as it provides a much simplified, one-pot process compared to processes of the prior art.

[0048]More specifically, the present invention relates to a process of encapsulating a hydrophobic active agent in a biodegradable polymer comprising dissolving a polymer in a halogen-free solvent that is at least partially water-miscible to form a polymer solution; adding a hydrophobic active agent to the polymer solution to form a drug phase contained in a vessel; adding a predetermined amount of an aqueous surfactant phase to the vessel containing the drug phase with mixing, said predetermined amount being sufficient to provide that the surfactant phase becomes the continuous phase and extraction medium in order to extract an amount of the solvent from the drug phase such that a suspension of microparticles is produced upon addition of the surfactant phase to the drug phase without requiring removal of solvent from the vessel.

Problems solved by technology

Many biologically active drugs possess strong lipophilic properties, which result in negligible solubility in water.

The development of an appropriate formulation of these active substances therefore is a challenging problem.

However, most all prior art processes use halogenated hydrocarbons as solvent (dichloromethane or chloroform), which have enormous toxicological potential (Henschler.

However, the solvent evaporation technique is often not preferred because active ingredient is often lost during the solvent extraction process.

However, the levels of incorporation of the hydrophilic active ingredient into the microspheres relative to the amounts employed in the process are fairly low and, moreover, this system involves a limitation with respect to the types of polymers which may be used given that it requires the polymer to be soluble in acetone, which is the case with lactic acid polymers, but which is not the case for lactic acid and glycolic acid copolymers.

This technique by emulsion / evaporation is therefore traditionally recognized as unsuitable for water-soluble peptides and for all water-soluble substances.

As already mentioned above, the employed halogenated solvents are also toxicologically objectionable.

This method also requires large amounts of surfactants.

Again, this process suffers primarily from loss of active ingredient due to denaturation.

The main disadvantage of this method is the use of large amounts of solvents with, in addition to cost constraints, problems of toxicity linked to the solvents, such as heptane, used.

This is because the techniques by coacervation using heptane do not enable its complete removal.

Independently of the above, it has also been observed that aggregates of microspheres causing a high loss of yield in the production of these microspheres by this method and sometimes requiring the total rejection of some batches which have thus become unusable, were often produced.

The tendency of the microspheres to aggregate causes additional difficulties at the time of suspending the microspheres for injection, in the case of injectable microspheres.

Another disadvantage of the technique by phase separation is the nonhomogeneous distribution of the active substance in the microspheres with irregular release, and in general a first phase of accelerated release (“burst effect”).

This is observed in particular when the active substance is suspended in the polymer solution, in particular because it is not soluble in the solvent for the polymer.

Additionally, problems include the formation of non-spherical particles, formation of particles that are not smooth and have defects, the presence of large particles with a wide range of sizes, and the presence of non-particulate material.

A serious shortcoming of these methods, however, is that the microparticles so produced consist of a mixture of monolithic microspheres and microcapsules.

This simultaneously also hampers reproducibility of product quality.

Moreover, the process involves a complex multistep process, in which the specific effect of individual process steps on product quality is uncertain, for which reason process optimization is also difficult.

The process is very time-intensive and requires large volumes of surfactant solutions.

Shortcomings of this method include the low yield (45% of the theoretically possible) and the high initial burst effect.

In addition, use of solvents, like dichloromethane and chloroform, leads to toxicologically objectionable residual solvent contamination in the end product.

This results in polymeric droplets containing the drug.

However, sensitive substances such as proteins can be inactivated during the process due to the elevated temperatures used and the exposure to organic solvent / air interfaces.

Further disadvantages include generation of high porosity due to rapid removal of the organic solvent.

Despite numerous modifications to the above processes to produce microparticles for pharmaceutical applications, problems remain which reduce the effectiveness and reproducibility of the microparticles produced by these methods, particularly for use in controlled release delivery systems.

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